Immunoregulation of Myelin Specific T Lymphocytes

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Multiple sclerosis (MS) is a devastating chronic, demyelinating autoimmune diseases of the central nervous system (CNS). Two key cytokines/chemokines thought to drive the early inflammatory stage of MS to a chronic progressive phase are macrophage Migration Inhibitory Factor (MIF) and its homolog D-Dopachrome Tautomerase (D-DT). Our laboratory designed two potent biological constructs called RTL1000 and a second- generation derivative, DRα1-MOG-35-55, that bind tightly to the MIF receptor, CD74, and competitively inhibit MIF binding and downstream signaling through phosphorylated extracellular-related kinase (pERK1/2). RTL1000/DRα1-MOG-35-55 also targets T cell receptors resulting in the inhibition of IL-2 release, T cell and macrophage activation and their migration into the CNS. Treatment of mice with experimental autoimmune encephalomyelitis (EAE – an animal model of MS) with DRα1-MOG-35-55 reduces the severity of both the acute and chronic forms of the disease when administered after onset of clinical signs and also promotes neuroprotection. New findings obtained during the previous Merit Review funding period have established several key facts that provide a solid basis for the studies proposed in this resubmission, including: 1) Detailed understanding of MIF and D-DT molecular interactions with their common receptor, CD74 and their contributions to acute and chronic EAE disease severity; 2) Discovery and characterization of DRQ, an ~8-fold more potent variant of DRα1-MOG-35-55 called DRhQ, [DRα1(L50Q)-human (h)MOG-35-55] for human clinical trials and its homolog, DRmQ, [DRα1(L50Q)-mouse (m)MOG-35-55] that was created for use in rodents; and 3) Demonstration that DRmQ treatment of acute and chronic EAE not only blocks signaling through the MIF/CD74 axis and the T cell receptor, but also inhibits additional proinflammatory pathways and promotes neuroprotection. The hypothesis to be addressed in this renewal application is that DRQ can inhibit inflammatory innate and adaptive immune pathways and simultaneously stimulate remyelination and neuronal protection. The major goals of the current grant application are to evaluate possible proinflammatory interactions between the MIF/CD74 axis with the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway in EAE; and to determine if DRmQ can block TREM-1, CXCR2 (which inhibits oligodendrocyte precursor proliferation) and the TCR and simultaneously enhance three neuroprotective pathways involving TREM-2 and several chemokine ligand and receptor pairs that were implicated in cytokine/chemokine screening studies. This triad spectrum of DRQ inhibition of MIF/CD74, TREM-1 and encephalitogenic T cell activity coupled with its stimulatory effects on CNS remyelination and axonal health in EAE will validate the unique therapeutic potential of DRhQ for MS and allow this novel “designer” drug to compete favorably with current and future monoclonal antibody and other currently approved therapies for MS that are directed at single target molecules.